Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].Cl.O(N)C.[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:30]Cl)[N:23]([CH2:24][C:25]3([OH:29])[CH2:28][CH2:27][CH2:26]3)[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1.Cl.ClCC1N(CC(C)C)C2C(C)=C(C)N=C(N)C=2N=1>>[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:30][N:3]([O:4][CH3:5])[CH3:2])[N:23]([CH2:24][C:25]3([OH:29])[CH2:28][CH2:27][CH2:26]3)[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CNOC
Reactant: Nc1nc2ccccc2c2c1nc(CCl)n2CC1(O)CCC1
Agent: CON
Agent: Cc1nc(N)c2nc(CCl)n(CC(C)C)c2c1C
Agent: Cl
Product: CON(C)Cc1nc2c(N)nc3ccccc3c2n1CC1(O)CCC1

Procedure:
1-[(4-Amino-2-{[methoxy(methyl)amino]methyl}-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanol was prepared according to the general methods of Part I of Example 9 using N,O-dimethyl hydroxylamine hydrochloride in lieu of methoxylamine hydrochloride and using 1-{[4-amino-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclobutanol in lieu of 2-(chloromethyl)-1-isobutyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine hydrochloride. The crude product was purified by HPFC eluting with a gradient of 0-35% CMA in chloroform and then recrystallized from acetonitrile to provide pure product as a white powder, mp 219.0-221.0° C. Anal. Calcd for C18H23N5O2 C, 63.32; H, 6.79; N, 20.51. Found: C, 63.12; H, 6.56; N, 20.16.
Reaction SMILES: Cl.[CH:2]1([N:6]2[CH2:11][CH2:10][CH:9]([CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:20]=[CH:21][C:22]([C:25](Cl)=[O:26])=[N:23][CH:24]=4)[CH2:15][CH2:14]3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1.[CH3:28][NH2:29]>ClCCl.O1CCCC1>[CH:2]1([N:6]2[CH2:11][CH2:10][CH:9]([CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([NH:29][CH3:28])=[O:26])=[N:23][CH:24]=4)[CH2:15][CH2:14]3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1
Reactant: CN
Reactant: O=C(Cl)c1ccc(N2CCC(CC3CCN(C4CCC4)CC3)CC2)cn1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(N2CCC(CC3CCN(C4CCC4)CC3)CC2)cn1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
5-{4-[(1-Cyclobutyl-4-piperidinyl)methyl]-1-piperidinyl}-2-pyridinecarbonyl chloride hydrochloride (may be prepared as described in Example 11, step 1) was dissolved in dichloromethane (10 ml) and added dropwise to a stirred solution of methylamine (1.57 ml of a 2M solution in tetrahydrofuran) in dichloromethane (10 ml) cooled to 0° C. over 1 h. The reaction was allowed to stir for a further 3 h before the mixture was evaporated. Chromatography (silica gel, eluting with methanol/dichloromethane, 0-20%) afforded the title compound (E11) (0.13 g). MS electrospray (+ion) 371 (MH+).1H NMR δ (CDCl3): 8.14 (1H, d, J=2.8 Hz), 8.01 (1H, d, J=8.8 Hz), 7.75 (1H, m), 7.19 (1H, dd, J=2.8, 8.8 Hz), 3.80 (2H, m), 3.00 (4H, m), 2.82 (3H, m), 2.19-1.21 (21H, m obscured by H2O)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2([C:11]#N)[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.CC(C[AlH]CC(C)C)C.C(OCC)(=[O:24])C.OS(O)(=O)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2([CH:11]=[O:24])[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: N#CC1(c2ccnc(Br)c2)CC1
Reactant: CCOC(C)=O
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: O=CC1(c2ccnc(Br)c2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2-bromo-pyridin-4-yl)-cyclopropanecarbonitrile (1.16 g, 5.20 mmol) in toluene (30 mL) is added DIBAL-H (10.4 mL, 1M in toluene) at −78° C. The mixture is stirred 1 hour at −78° C. and warmed to room temperature. After 1 hour, ethyl acetate (30 mL) is added, followed by 1M aqueous solution of H2SO4 (30 mL). Phases are separated and the aqueous layer is extracted with ethyl acetate (3×50 mL). The combined organic layers are dried over MgSO4, filtered and concentrated to afford crude 1-(2-bromo-pyridin-4-yl)-cyclopropanecarbaldehyde (ES+ m/z 226.48; 228.47), which is used without purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]([CH3:16])([C:10]1[NH:14][C:13](=[O:15])[O:12][N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].CO.[C:20]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]([CH3:9])([C:10]1[N:14]([CH3:20])[C:13](=[O:15])[O:12][N:11]=1)[CH3:16])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1noc(=O)[nH]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(C(C)(C)NC(=O)OC(C)(C)C)noc1=O
Temperature: 2.5 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
To a colorless solution of [1-methyl-1-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-ethyl]-carbamic acid tert-butyl ester (1.5 g, 6.17 mmol) in THF (30.0 mL) was added methanol (296 mg, 374 μl, 9.25 mmol) and triphenylphosphine (1.94 g, 7.4 mmol). The mixture was cooled to 0-5° C. and diisopropyl azodicarboxylate (1.5 g, 1.46 ml, 7.4 mmol) was added slowly over a period of 20 minutes at max: 5° C. The mixture was stirred for another 30 minutes at 0-5° C. and for 16 hours at room temperature. Solvents were removed in vacuo and the residue was purified by flash chromatography (silica gel, 70 g, 0% to 100% ethyl acetate in heptane) to give the title compound (1.4 g, 89%) as white solid; GC-MS (EI) 98%, 257.0 (M)+.
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]=[C:9]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:8]=1.[C:27](Cl)(=[O:33])[CH:28]=[CH:29][CH:30]=[CH:31][CH3:32]>C(N(CC)CC)C>[NH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]=[C:9]([N:21]2[CH2:26][CH2:25][N:24]([C:27](=[O:33])[CH:28]=[CH:29][CH:30]=[CH:31][CH3:32])[CH2:23][CH2:22]2)[N:8]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: CC=CC=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC=CC=CC(=O)N1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
To 20 ml of tetrahydrofuran were added 1.16 g of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline and 1.5 g of triethylamine. There was then added 0.52 g of 2,4-hexadienoyl chloride, after which the mixture was stirred at room temperature for 3 hours. The reaction mixture was then concentrated by evaporation under reduced pressure, and the resulting residue was washed with water and recrystallized from ethanol, to give 1.3 g of the desired Compound No. 10 in the form of pale yellow powdery crystals melting at 231°-233° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][N:12]1[CH2:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)=[CH:5]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:12]1([CH2:11][C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCCN(Cc2cc3cc(F)ccc3[nH]2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc2[nH]c(CN3CCCNCC3)cc2c1
Reaction time: 1 h

Procedure:
The product from Example 11B (0.48 g, 1.40 mmol) in CH2Cl2 (20 mL) was treated with TFA (20 mL) and stirred for 1 hour. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (10% MeOH/CH2Cl2/1% NH4OH) to provide the title compound. 1H NMR (CD3OD, 300 MHz) δ 1.85–1.98(m, 4H), 2.58–2.68(m, 2H), 3.45–3.57 (m, 4H), 3.67(s, 2H), 6.25(s, 1H), 6.75–6.90(m, 1H), 7.10–7.25(m, 2H); MS (DCI/NH3) m/z 248 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C@@H:7]2[N:22]([CH3:23])[C@H:11]([CH2:12][C:13]=1OS(C(F)(F)F)(=O)=O)[CH2:10][N:9]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:8]2)=[O:5])[CH3:2].[Cl:31][C:32]1[C:37]([F:38])=[CH:36][CH:35]=[C:34]([F:39])[C:33]=1[C:40]1[CH:44]=[C:43]([CH2:45][O:46][C:47]2[CH:52]=[CH:51][C:50](B3OC(C)(C)C(C)(C)O3)=[CH:49][N:48]=2)[O:42][N:41]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C@@H:7]2[N:22]([CH3:23])[C@H:11]([CH2:12][C:13]=1[C:50]1[CH:49]=[N:48][C:47]([O:46][CH2:45][C:43]3[O:42][N:41]=[C:40]([C:33]4[C:34]([F:39])=[CH:35][CH:36]=[C:37]([F:38])[C:32]=4[Cl:31])[CH:44]=3)=[CH:52][CH:51]=1)[CH2:10][N:9]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:8]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]1N2C
Reactant: CC1(C)OB(c2ccc(OCc3cc(-c4c(F)ccc(F)c4Cl)no3)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(c2ccc(OCc3cc(-c4c(F)ccc(F)c4Cl)no3)nc2)C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]1N2C
Temperature: 80 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
(rac.)-(1R*,5S*)-9-Methyl-7-trifluoromethanesulfonyloxy-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6-dicarboxylic acid 3-tert-butyl ester 6-ethyl ester (WO 2003/093267; 1.00 g, 2.18 mmol) and 2-[3-(2-chloro-3,6-difluoro-phenyl)-isoxazol-5-ylmethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (1.41 g, 3.27 mmol) were dissolved in DME (14.5 mL), and aq. 2M Na2CO3 (11.0 mL) was added. The mixture was degassed with N2 (5 min). Pd(PPh3)4 (126 mg, 0.109 mmol) was added, and the mixture was rapidly heated to 80° C. The mixture was stirred at this temperature for 1 h, and was allowed to cool to rt. The mixture was diluted with EtOAc (100 mL), and was washed with water (100 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC(CH2Cl2/MeOH 95:5) yielded the title compound (1.12 g, 81%). LC-MS: tR=0.91 min; ES+: 631.34.
Reaction SMILES: [Br:1][C:2]1[C:16]([C:17]([OH:19])=O)=[C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:9][C:5]2=[CH:4][CH:3]=1.Cl.Cl.[NH2:22][CH:23]1[CH2:30][CH:29]2[N:31]([CH3:32])[CH:25]([CH2:26][CH2:27][CH2:28]2)[CH2:24]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[CH3:32][N:31]1[CH:25]2[CH2:26][CH2:27][CH2:28][CH:29]1[CH2:30][CH:23]([NH:22][C:17]([C:16]1[C:2]([Br:1])=[CH:3][CH:4]=[C:5]3[O:9][C:8]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)=[N:7][C:6]=13)=[O:19])[CH2:24]2
Reactant: O=C(O)c1c(Br)ccc2oc(-c3ccccc3)nc12
Reactant: CN1C2CCCC1CC(N)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1C2CCCC1CC(NC(=O)c1c(Br)ccc3oc(-c4ccccc4)nc13)C2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 12.2 %

Procedure:
A mixture of 5-bromo-2-phenylbenzo[d]oxazole-4-carboxylic acid (180 mg, 0.56 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (152 mg, 0.67 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (215 mg, 1.12 mmol) and 1-hydroxybenzotriazole (151 mg, 1.12 mmol) in DMF (2.5 mL) was stirred for 5 min at room temperature, then triethylamine (0.31 mL, 2.24 mmol) was added. The resulting reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with dichloromethane (20 mL), then washed with a saturated solution of sodium bicarbonate (10 mL). The aqueous layer was further extracted with dichloromethane (3×15 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 89:10:1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-5-bromo-2-phenylbenzoxazole-4-carboxamide (31 mg, 12%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 8.25-8.23 (m, 2H), 7.62 (d, J=8.5 Hz, 1H), 7.60-7.53 (m, 3H), 7.48 (d, J=8.5 Hz, 1H), 7.12 (br s, 1H), 4.69-4.63 (m, 1H), 3.13 (d, J=10.0 Hz, 2H), 2.67 (td, J=12.5, 7.0 Hz, 2H), 2.54 (s, 3H), 2.05-1.93 (m, 3H), 1.60-1.52 (m, 1H), 1.43 (t, J=11.0 Hz, 2H), 1.15-1.10 (m, 2H); MS (ESI+) m/z 454 (M+H); HPLC 98.4% (AUC), tR=11.89 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:15]([OH:17])=[O:16])[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:30](O)[CH2:31][OH:32]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:15]([OH:17])=[O:16])[CH2:9][CH2:10][C:11]2([O:32][CH2:31][CH2:30][O:14]2)[CH2:12][CH2:13]1
Reactant: OCCO
Reactant: O=C1CCC(C(=O)O)(c2ccccc2F)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)C1(c2ccccc2F)CCC2(CC1)OCCO2

Procedure:
1-(2-Fluorophenyl)4-oxocyclohexane-1-carboxylic acid (D3, 16.36 g, 69 mmol) was stirred with toluene-4-sulphonic acid hydrate (0.50 g, 3 mmol) and 1,2-ethanediol (35 ml) at reflux in toluene (500 ml), removing the immiscible 1,2-ethanediol/water distillate via a Dean-Stark trap until the distillate was homogenous. The solution was then evaporated, dissolved in ethyl acetate, washed with water and brine, dried (Na2SO4) and evaporated to give the title compound (19.94 g, quantitative) as an amber syrup, contaminated with some unidentified materials (NMR).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[Li]CCCC.N1([CH:25]=[O:26])CCCCC1.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[C:8]1([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH:25]=[O:26])[CH:7]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=CN1CCCCC1
Reactant: Brc1cc(-c2ccccc2)ccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=Cc1cc(-c2ccccc2)ccn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A cooled (−78° C.) solution of commercially available 2-bromo-4-phenylpyridine (500 mg; 2.13 mmol) in anh. THF (9 ml) was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (1.33 ml; 2.13 mmol), and the resulting mixture was further stirred at −78° C., under nitrogen, for 1 h. Commercially available piperidine-1-carbaldehyde (483 mg; 4.27 mmol) was added dropwise to the cooled (−78° C.) reaction mixture, and stirring was continued at −78° C. for 15 min., and then at 0° C. for 1 h. Aq. sat. NH4Cl (25 ml) and AcOEt (50 ml) were added, and the separated organic layer was further washed with brine (20 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (toluene/AcOEt=7/3) afforded 4-phenylpicolinaldehyde as a yellow solid. LC-MS (conditions A): tR=0.43 min.; [M+H]+: 184.48 g/mol.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[NH:10][C@@H:11]([CH3:28])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][C:23]([C:25](=O)[NH2:26])=[CH:22][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]1[CH2:45][CH2:44]N[CH2:42][CH2:41]1>ClCCl>[CH2:1]([O:8][C:9](=[O:29])[NH:10][C@@H:11]([CH3:28])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][C:23]([CH2:25][N:26]4[CH2:44][CH2:45][N:40]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=5)[CH2:41][CH2:42]4)=[CH:22][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](Cn1ncc2ccc3oc(C(N)=O)cc3c21)NC(=O)OCc1ccccc1
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: C[C@@H](Cn1ncc2ccc3oc(CN4CCN(c5ccccn5)CC4)cc3c21)NC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
A solution of the product from Example 3, Step B (0.18 g, 0.475 mmol) in dichloromethane (20 mL) was cooled (ice bath) and thionyl chloride (0.052 mL, 0.71 mmol) added. The mixture was stirred for 30 min and then evaporated to a residue which was dissolved in dichloromethane (20 mL); this solution was evaporated and the residue dried under a vacuum. The residue was dissolved in dichloromethane (20 mL) and 1-(2-pyridyl)piperazine (0.5 mL, 3.4 mmol) was added, and the mixture was stirred at room temperature for one hour at which point additional 1-(2-pyridyl)piperazine (0.9 mL) was added. Solvent was removed by evaporation (45° C.) and THF (10 mL) was added, followed by heating the mixture at reflux temperature for one hour. This reaction mixture was evaporated and the residue dissolved in methanol (25 mL) and triethylamine (1.5 mL) followed by evaporation of this mixture to a residue which was purified by chromatography (silica gel, hexane/ethyl acetate) to give a foamy solid (0.21 g, 84%): LC/MS m/z 525 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[NH2:27][C@@H:28]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=1)[C:29]([NH:31][C:32]1[CH:33]=[N:34][C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH:9]([C:10](=[O:12])[NH:27][C@H:28]([C:29](=[O:30])[NH:31][C:32]1[CH:33]=[N:34][C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@@H](Cc1ccc(C(F)(F)F)cc1)C(=O)Nc1cnc2ccccc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)C(=O)Nc1cnc2ccccc2c1
Reaction time: 8 h

Procedure:
To a solution of 2-{[(tert-butoxy)carbonyl]amino}-3-ethoxy-3-oxopropanoic acid XCVII (0.5 g; 2.02 mmol) and DIPEA (1.20 mL; 7.07 mM) in DCM (30 mL) was added (2S)-2-amino-N-(quinolin-3-yl)-3-[4-(trifluoromethyl)phenyl]propanamide LXXI (0.88 g; 2.02 mmol) and TBTU (0.68 g; 2.12 mmol). The reaction mixture was stirred overnight, diluted with DCM (30 mL), washed with 1 M aq NaOH (2×), 1 M aqueous HCl (2×), brine and dried over anhydrous MgSO4. The solvent was evaporated and the crude product was crystallized from DCM/hexane to give ethyl 2-{[(tert-butoxy)carbonyl]amino}-2-{[(1S)-1-[(quinolin-3-yl)carbamoyl]-2-[4-(trifluoromethyl)phenyl]ethyl]carbamoyl}acetate XCVIII as yellow crystals (0.90 g, 1.53 mmol, 76% yield). ESIMS found for C29H31F3N4O6 m/z 589 (M+H).
Reaction SMILES: [NH2:1][C@H:2]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].[C:13]([O:17][C:18]([NH:20][C:21]1([C:36](O)=[O:37])[CH2:26][CH2:25][N:24]([C:27]2[C:28]3[CH:35]=[CH:34][NH:33][C:29]=3[N:30]=[CH:31][N:32]=2)[CH2:23][CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CC(N(C)C)=O>[Br:12][C:9]1[CH:8]=[CH:7][C:6]([C@@H:2]([NH:1][C:36]([C:21]2([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:15])([CH3:14])[CH3:16])[CH2:22][CH2:23][N:24]([C:27]3[C:28]4[CH:35]=[CH:34][NH:33][C:29]=4[N:30]=[CH:31][N:32]=3)[CH2:25][CH2:26]2)=[O:37])[CH2:3][CH2:4][OH:5])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: N[C@@H](CCO)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](CCO)c2ccc(Br)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 20 °C
Reaction time: 24 h
Yield: 44.5 %

Procedure:
(S)-3-Amino-3-(4-bromophenyl)propan-1-ol (Intermediate 51) (191 mg, 0.83 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (300 mg, 0.83 mmol) and DIPEA (0.435 mL, 2.49 mmol) in DMA (5 mL). O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (347 mg, 0.91 mmol) was added and the resulting solution was stirred at 20° C. for 24 hours. The reaction mixture was evaporated to dryness then diluted with EtOAc (300 mL), and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 2 to 6% MeOH with ammonia in DCM. Fractions were evaporated to afford (S)-tert-butyl 4-(1-(4-bromophenyl)-3-hydroxypropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (212 mg, 44.5%) as a white solid. The product (212 mg, 0.36 mmol) was suspended in dioxane (5.00 mL) and 4M hydrogen chloride in dioxane (0.577 mL, 16.6 mmol) added. The reaction was stirred at ambient temperature for 2 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 3.5N ammonia/MeOH and pure fractions were evaporated to dryness. The product was then purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 μm silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (S)-4-amino-N-(1-(4-bromophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (51.0 mg, 13.0%) as a white solid.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[N+:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([O-])=O.[CH3:13][OH:14]>>[C:7]1([NH:4][C:13](=[O:14])[O:3][CH2:1][CH3:2])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:4][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: CO
Reactant: CCO
Product: CCOC(=O)Nc1ccccc1
Product: Nc1ccccc1

Procedure:
The procedure was the same as for Example 2 with the exception that ethanol was substituted for methanol on an equal volume basis. Complete conversion of the nitrobenzene occurred in 4.5 hours at 160° C. and yielded 0.014 mole ethyl N-phenylcarbamate, and 0.058 mole additional aniline (0.108 mole total aniline). The balance (0.023 mole) appeared as by-products derived from aniline. It is thus clear that the selectivity of the ruthenium catalyzed conversion of nitrobenzene and methanol to methyl N-phenylcarbamate is higher than the selectivity of the corresponding conversion of nitrobenzene and ethanol to ethyl N-phenylcarbamate even when aniline is added in order to improve the selectivity.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1I.C([Mg][Cl:14])(C)C.[CH3:15][N:16]([CH:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1=[O:25])[CH3:17].[Cl-].[NH4+]>CCOCC>[ClH:14].[CH3:17][N:16]([CH:18]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[S:2][CH3:1])[OH:25])[CH3:15]
Reactant: CN(C)C(c1ccccc1)C1CCCCC1=O
Reactant: CSc1ccccc1I
Reactant: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CSc1ccccc1C1(O)CCCCC1C(c1ccccc1)N(C)C
Product: Cl
Temperature: -10 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
0.811 g (3.24 mmole) of 2-methylmercaptoiodobenzene were dissolved in 2 ml of ether, cooled to −10° C., and 1.62 ml (3.24 mmole) of isopropylmagnesium chloride (2 M solution in tetrahydrofuran) were added dropwise. After stirring for one hour at ° C., 0.50 g (2.16 mmole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 and dissolved in 2 ml of ether was added dropwise, and the whole was stirred for 15 hours at RT. The reaction mixture was worked up by adding 2 ml of saturated ammonium chloride solution while cooling in an ice bath and was extracted three times at RT with 5 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 0.84 g of crude base (109% of theory) was obtained, from which 0.483 g of 2-(dimethylaminophenyl-methyl)-1-(2-methylsulfanylphenyl)cyclohexanol, hydrochloride (38.0% of theory) was obtained according to the procedure described in Example 1 (3rd Stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 230° C.